Endotoxin (lipopolysaccharide: LPS), which is a membrane component of bacteria, acts on cells such as monocytes, macrophages, and vascular endothelial cells, induces the overproduction of various inflammatory mediators such as TNF-α and the like, causes sudden hypotension, blood coagulation disorders, circulatory disturbances, and the like in addition to systemic inflammatory responses, and thus develops sepsis (see, for example, Non-patent document 2). Lipopolysaccharide and Lipid A, which corresponds to a partial structure thereof, activate intracellular signal transduction via TLR4 (Toll-like receptor 4), which is a functional cell surface receptor, after binding with CD14 (see, for example, Non-patent document 3), whereby various cell responses represented by the production of inflammatory mediators are initiated. Therefore, it is considered that a substance capable of suppressing the intracellular signal transduction or cell activation induced by endotoxin, and various cell responses, which are induced by such intracellular signal transduction or cell activation and represented by the overproduction of inflammatory mediators such as TNF-α, can be effective prophylactic and therapeutic agents for sepsis (see, for example, Non-patent documents 3 and 4, and Patent documents 1 and 2).
Intracellular signal transduction or cell activation induced by endotoxin, and various cell responses such as the overproduction of inflammatory mediators including TNF-α, etc. induced by the intracellular signal transduction or cell activation lead to development and progress of various diseases such as ischemic brain disorder, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complications, arthritis, osteoporosis, osteopenia, autoimmune diseases, tissue disorders and rejection after organ transplantation, bacterial infection, viral infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis, and leukemia, in addition to the above-described sepsis (for example, Non-patent document 5 and Patent document 3).
The present inventors made intensive studies in order to solve the above problems, and as a result, they found that there are a group of compounds having a desired effect among substituted cycloalkene derivatives (Patent document 4). However, substituted cycloalkene derivatives (in the free form) are amorphous and have hygroscopicity. In view of this, the present inventors studied pharmacologically acceptable salts thereof. However, it was not easy to find crystals having storage and handling stability, and therefore industrialization thereof was extremely difficult.